Abstract

5298

The CD44 transmembrane glycoproteins are implicated in matrix adhesion, migration, growth promotion, and survival. Previously, we have shown that both OPN and CD44 variant isoforms are frequently overexpressed in gastric cancer (GC), and that OPN-CD44V interaction promotes ECM-derived survival signal mediated through integrin activation, demonstrating an important role of OPN-CD44V interaction in the pathogenic development and progression of GC. This study aims to dissect the molecular mechanisms that mediate the adhesion and survival functions of CD44. We showed that ligation of CD44 by antibody cross-linking induces the re-distribution of CD44, Src, PTP-α and integrins to colocalize with GM-1 and caveolin-1 in lipid rafts. Integrins are activated through an inside-out mechanism via Src, which is activated and in complex with CD44 in rafts. Through integrin activation, CD44-expressing cells display enhanced cell adhesion and ECM-derived survival. Treatment of cells with cholesterol chelator MβCD or ectopically expression of non-raft targeting mutants of CD44 abolished Src activity in rafts but has little effect on non-raft Src activity, leading to concomitant blockage of integrin activation, and CD44-elicited cell adhesion and survival. It appears that palmitoylation and intracellular protein interactions both are involved in targeting CD44 to lipid rafts. Collectively, our findings show that CD44, known as an adhesion molecule, works as a signaling regulator that induces lipid raft reorganization eliciting the establishment of specific signaling complexes to promote cell survival through increased cell adhesion.